Systems and methods for treatment of fungus

ABSTRACT

Provided herein are systems, devices and methods for the treatment of fungus. In particular, provided herein are systems, devices and methods employing energy to nail and tissue structures to treat fungal infection.

The present application is a continuation of U.S. Pat. ApplicationSerial Number 16/082,146, filed Sep. 4, 2018, which is a §371 NationalEntry of PCT/US2017/020659, filed Mar. 3, 2017, which claims priority toU.S. Provisional Pat. Application Serial Number 62/303,742, filed Mar.4, 2016, the disclosure of which is herein incorporated by reference inits entirety.

FIELD

Provided herein are systems, devices and methods for the treatment offungus. In particular, provided herein are systems, devices and methodsemploying energy to nail and tissue structures to treat fungalinfection.

BACKGROUND

Nail fungus, also known as onychomycosis or tinea unguium, is a commoninfection that often begins as a discolored spot under the tip of afingernail or toenail. As the infection progresses, nail fungus causesthe nail to discolor, thicken and crumble at the edge. Nail fungalinfections are typically caused by a dermatophyte fungus. Yeasts andmolds also can be responsible for nail fungal infections.

Signs of nail fungus include thickened, brittle, crumbly, or raggednails that are distorted in shape and white or yellow in color. Infectednails also may separate from the nail bed, a condition calledonycholysis. A severe case of nail fungus can be painful and may causepermanent damage to the nails. Nail fungus may lead to other seriousinfections that spread beyond the hands or feet, particularly for thosewith a suppressed immune system due to medication, diabetes or otherconditions.

Risk factors for infection of the nail by fungus include having a familyhistory of onychomycosis, having athlete’s foot, heavy perspiration,wearing footwear that hinders ventilation, living with someone that hasnail fungus, being exposed to damp communal areas, and working in humidor moist environments. The risk of onychomycosis increases withincreasing age and is more common in males than females. Other factorsthat predispose to nail fungal infection include having recent nailinjury, psoriasis or other nail disorders, circulation problems,weakened immune system, or Down syndrome.

Existing treatments are highly unsatisfactory even though over a billiondollars a year is spent on oral and topical prescriptions. Oralantifungal drugs include terbinafine (LAMISIL) and itraconazole(SPORANOX). The drugs are typically taken for six to twelve weeks andresults, if achieved, take months to observe. Treatment success rateswith these drugs appear to be lower in adults over age 65. Importantly,oral antifungal drugs can cause serious side effects ranging from skinrash to liver damage. As such, these drugs may be contraindicated forpatients with liver disease or congestive heart failure or those takingcertain medications. Available topical treatments include medicated nailpolishes (e.g., ciclopirox, aka PENLAC) and liquids (efinconazole, akaJUBLIA). The effectiveness of these treatments is limited.

Surgical and laser- and light-based approaches have also been used.Surgical approaches include nail removal. This is a painful procedurerequiring weeks of dressing changes and management with pain medication.A new nail grows back very slowly (typically 12-18 months for a new bigtoenail) and may be permanently abnormal in shape and thickness. Laserand light approaches are newer and have not demonstrated effectivenessin curing nail fungus. They are also not available everywhere, areexpensive, painful and typically not covered by insurance.

People have also attempted home remedies, which have limited to noeffectiveness. These include over-the-counter antifungal nail creams andointments, use of VICKS VAPORUB, personal mechanical trimming orthinning of nails, use of snakeroot extract, and use of tea tree oil.

In summary, no broadly effective treatment has been identified toaddress this common and significant public health concern. The mosteffective approaches to date have potential serious side effectsincluding liver failure. New solutions are needed to the unsolvedproblem.

SUMMARY

Provided herein are systems, devices and methods for the treatment offungus. In particular, provided herein are systems, devices and methodsemploying energy to nail structures or other keratinized surfaces totreat fungal infection. While toe and finger nails are illustratedherein, it should be understood that the systems, devices, and methodsmay be used with any keratinized tissue, including skin and hair.

In some embodiments, a system is provided. In some embodiments, thesystem comprises an energy source (e.g., generator) and an energydelivery device (e.g., comprising an antenna that emits energy whenattached to said energy source). In some embodiments, the energy sourceis a radio-frequency (e.g., microwave) generator.

In some embodiments, the energy delivery device is configured to attachto or fit around an appendage (e.g., toe, finger) of a subject. In someembodiments, the device has an attachment component having top andbottom portions configured to receive an appendage (e.g., toe)therebetween. For example, in some embodiments, the attachment componentis a clip with a top portion fitting above an appendage and a bottomportion fitting below an appendage. In some embodiments, the attachmentcomponent comprises a sheath that fits around the appendage. In someembodiments, the device is configured to receive multiple appendagessimultaneously.

In some embodiments, the antenna is positioned in the device on the topportion side such that it is positioned above a nail when an appendageis received in the device. In some embodiments, the device comprises oneor more dielectric layers. In some embodiments, the device has adielectric layer below the antenna (e.g., positioned such that itdirectly makes contact with a toenail when a toe is received in thedevice). In some embodiments, an additional layer (e.g., sterile film,etc.) is positioned between this dielectric layer and the nail. In someembodiments, one or more dielectric layers are positioned above theantenna (i.e., between the antenna and the top portion of the attachmentcomponent). In some embodiments, the one or more dielectric layersinclude one or more or all of: a first dielectric layer above theantenna (e.g., of similar or identical material and dimension to thedielectric layer below the antenna); a nail like dielectric layer (e.g.,toenail like) above the first dielectric layer (e.g., dimensioned tomimic a toenail; and of the same or different material as the firstdielectric layer); and a nail-bed like dielectric layer (e.g.,dimensioned to mimic a nail bed; and of the same or different materialas the first dielectric layer and/or toenail like dielectric layer).

In some embodiments, the device further comprises one or more thermalsensors. In some embodiments, the thermal sensors are located within thenail bed like dielectric material. In some embodiments, the systemcomprises a temperature monitoring component that at intervals or inreal-time or near real-time monitors temperature and notifies a user ofthe temperature or automatically manages energy delivery (e.g., loweringdelivery, shutting off energy, increasing delivery) in response toundesired temperatures.

In some embodiments, the system comprises a user interface. In someembodiments, the user interface comprises a computer processor,software, and a display that allow the user to select system parametersand to receive feedback during a procedure.

Devices comprising any of the system components are further providedherein.

Use of such devices or system (e.g., to treat toenail fungus) are alsoprovided herein.

In some embodiments, provided herein are methods of treating anappendage (e.g., toe, finger) having nail fungus, comprising: attachingan energy delivery device comprising an antenna to the appendage anddelivering energy to a nail bed of the appendage. In some embodiments,the device/system is configured to deliver energy substantially to thenail bed, such that delivered energy kills or inhibits the growth oftoenail fungus causing organisms without damaging or harming tissue ofthe appendage or damaging or harming the nail.

In some embodiments, killing of toenail fungus causing organismscomprises at least a 20% (e.g., 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%,etc.) reduction in organism. Any suitable assay may be employed tomeasure organisms, including but not limited to, molecular techniques,culturing, and microscopy (see e.g., Paugam et al., J. Microbiol.Methods, 95(2):218-222 (2013), herein incorporated by reference in itsentirety).

BRIEF DESCRIPTION OF THE DRAWINGS

The above and other aspects, features, and advantages of the presentdisclosure will become more apparent in light of the following detaileddescription when taken in conjunction with the accompanying drawings inwhich:

FIG. 1 is a schematic diagram of a nail fungus treatment systemaccording to an embodiment of the present disclosure;

FIG. 2 is a schematic diagram of a nail fungus treatment deviceaccording to an embodiment of the present disclosure;

DETAILED DESCRIPTION

Provided herein are systems, devices and methods for the treatment offungus. In particular, provided herein are systems, devices and methodsemploying energy to nail and tissue structures to treat fungalinfection.

Any type of fungus or fungal infected tissue or nail may be treated bythe systems, devices, and methods described herein. In some embodiments,the nail is on an appendage such as a toe or finger (i.e., toenails orfinger nails). In some embodiments, the nail is treated at an earlystage of fungal infection or prophylactically prior to infection. Insome embodiments, the nail is treated at any various stage of infection,including severe infections where significant nail damage has alreadyoccurred.

In some embodiments, the treated subject is a human. However, thesystems, devices, and methods find use in veterinary application fortreatment of companion animals (e.g., dogs, cats), livestock (e.g.,including treatment of fungal infections in hooves or surroundingtissue, zoo animals, wild animals, and the like). Human subjects includeboth adults and children. Human may be selected based on risk factors,including but not limited to age, heavy perspiration, being male, familyhistory, working in humid or moist environments, wearing footwear thathinders ventilation, living with someone that has nail fungus, exposureto damp communal areas, having athlete’s foot, having skin or nailinjury, having psoriasis, circulation problems, weakened immune system,or Down syndrome.

The energy delivery provides a mechanism that is able to kill and/orinhibit the growth of a wide variety of organisms associated with nailfungus, onychomycosis, or related conditions. In some embodiments, thetargeted organism is a dermatophyte (e.g., Trichophyton rubrum, T.interdigitate, Epidermophyton floccosum, T. violaceum, Microsporumgypseum, T. tonsurans, T. soudanense), Candida, or a nondermatophyticmold (Neoscytalidium, Scopulariopsis, and Aspergillus), or combinationsthereof.

Treatment times and intervals may be selected based on the subject’sneeds. In some embodiments, one treatment is provided. In someembodiments, two or more treatments are provided (e.g., 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, ..., 20, ... chronic). Treatments may be spacedapart by minutes, hours, days, weeks, months, or years.

In some embodiments, the result of treatment is partial to completeclearance of infection (e.g., greater than 10%, 20%, 30%, 40%, 50%, 60%,70%, 80%, 90%, 95%, 98%, 99% clearance or reduction as measured by anysuitable assay, including but not limited to, culture, KOH prep,calcofluor white stain, molecular tests, antigen testing, nail surfaceappearance, nail lost regrowth, etc.).

In some embodiments, there is minimal loss (e.g., no reversible loss) tono loss of healthy tissue, nail plate, or nail bed in response to theenergy delivery.

In some embodiments, the energy delivery is combined with other existingtherapies as a combination therapy. Such therapies include, but are notlimited to, oral antifungal drugs (e.g., terbinafine, itraconazole),topical treatments (e.g., ciclopirox), mechanical treatments, andsurgical and laser treatments.

Particular embodiments of the present disclosure are described hereinbelow with reference to the accompanying drawings. In the followingdescription, well-known functions or constructions are not described indetail to avoid obscuring the present disclosure in unnecessary detail.

FIG. 1 shows an energy delivery system comprising an energy deliverydevice 500 connected by a cable 510 to an energy source 700. In someembodiments, the energy delivery source 700 is a radio-frequency (RF)generator (e.g., a microwave generator). The energy source may compriseor consist of a tunable or fixed-frequency oscillator (eithergeneral-purpose laboratory-grade, e.g. from Keysight Technologies orAnritsu) or dedicated. Output powers from such oscillators may rangefrom -20 dBm to + 20 dBm or more, and frequency ranges may extend from0.01 GHz to 20 GHz or more. Power from the oscillator may be amplifiedby a suitable solid-state power amplifier having gain of 1-20 dB or moreand output power of +10 dBm to +40 dBm (e.g., 10 Watts) or more. Thepower amplifier may be a commercially-available module or a customizedsingle- or multi-transistor module preferably located on or near to theapplicator to minimize the effect of power losses in the delivery.

In some embodiments, the cable 510 is a coaxial cable. In someembodiments the cable 510 is a plurality of cables either separate orbundled together or integrated (i.e., two functionalities in the samehousing). In some embodiments, the cable provides a coolant channel tocirculate coolant to the energy delivery device. In such embodiments, acoolant source (e.g., liquid coolant, gas such as CO₂) is provided (notshown). In some embodiments, the cable further comprises a transmissionline for transmitting data or other information to and from the energydelivery device to and from a control computer or component (not shown).

In some embodiments, the energy delivery device 500 has a top portion520 and a bottom portion 530. The top portion 520, when the device iscontacted with an appendage (e.g., toe or finger) 600 sits above thenail of the appendage. The bottom portion 530 is below the appendage. Insome embodiments, the top portion 520 and bottom portion 530 areconnected by a connector 540. The connector 540 may take any form thatconnects the top portion 520 and bottom portion 530. As shown in FIG. 1, the connector 540 attaches at a lower end to the bottom portion 530and at a top end to the upper portion 520. Multiple connectors may beemployed. The connector may include a spring or other tensioningcomponent that causes the top portion 520 and bottom portion 530 to bedirected towards one another by a force, such that the device clampsonto an object (e.g., finger, toe) inserted thereinbetween. Where suchforce is applied, the connector 540 may employ any of a variety ofmechanisms employing clips or clamps, including, but not limited to,tension/extension springs, compression springs, torsion springs,constant springs, variable springs, coil springs, flat springs, machinedsprings, serpentine springs, cantilevers, leaf springs, bands, bandclamp, bar clamp, C-clamp, set screw, spring clamp, and the like.

FIG. 2 shows an exemplary energy delivery device 500 in across-sectional view. The upper and lower portions are presented as aclip 180 on either side of a toe 100 (shown from an end view) having anailbed 110 and toenail 120. The upper portion of the energy deliverydevice has an antenna 140 with a conformal dielectric material 130 belowit (on the toenail side) and above it (on the clip side). The devicefurther has a toenail-like dielectric material 150 above the conformaldielectric material (here dimensioned similar to the toe nail) and anailbed-like dielectric material 160 above the toenail-like dielectricmaterial 150. Also shown are a plurality of thermal sensors 170.

The antenna 140 is preferably comprised of a foil or thin conductor (Cu,Al, Auplated Cu) formed in a single- or multi-resonant slot or bowtieconfiguration on a suitable dielectric substrate (Teflon, Kapton, FR-4,polyethylene). However, other types of antennas such as dielectricantenna may also be employed.

The conformal dielectric material 130, in some embodiments, may be agel, silicone, PDMS, or other suitable material with low dielectriclosses to maximize transfer of energy into the treatment zone.

A nail-like (e.g., toenail-like) dielectric material is combined with anailbed-like dielectric material to form a tissue phantom that mimicsthe properties of the treatment zone. Embedded temperature sensors inthis phantom treatment zone are thus able to witness and estimate thetemperature in the treatment zone (achieved via energy deposition).

The toenail-like dielectric material 150, in some embodiments, maycomprise or consist of FR-4, Kapton, polyethylene, Teflon, or the like,fashioned into dimensions similar to that of the nail under treatment.

The nailbed-like dielectric material 160, in some embodiments, maycomprise or consist of silicone, PDMS, gel, or other tissue-likematerial with dielectric properties (e.g. water content) and dimensionssimilar to that of the nailbed.

Any type or number of temperature sensors 170 may be employed. In someembodiments, no sensor is employed. In some embodiments, a single sensoris employed. In some embodiments, two or more sensors are employed. Thesensors may be wireless or wired and may employ any sensing mechanism.Contemplated sensors include, but are not limited to, thermistors,thermocouples, resistance thermometers, silicon bandgap temperaturesensor, and the like. In some embodiments, sensors measure indirectconsequences of temperature changes, such as pressure (e.g., pressuresensors) or displacement changes (e.g., due to swelling), for example,by assessing tension or displacement on a spring clip holding thetreatment device onto a digit. In some embodiments, a reflectometer isemployed. In some such embodiments, application of power is alternatedbetween treatment and sensing of local dielectric properties of thetreatment zone, enabling localized sensing of treatment progress (seee.g., Choi et al., Compact mixer-based 1-12 GHz reflectometer, in IEEEMicrowave and Wireless Components Letters, vol. 15, no. 11, pp. 781-783,November 2005, herein incorporated by reference in its entirety).

In use, the energy delivery device is fitted onto or around an appendageor appendages to be treated. The generator is activated by a user or bya computer processor running a programmed treatment regimen. Energy isdelivered to the energy delivery device from the generated to treat thetissue harboring the pathogen. In some embodiments, energy deliverycomprises: a dose and schedule ranging from 0.1 W to 10 W or more,delivered in a variable-duty-cycle format for durations of 1 second to3600 seconds or more, limited by the tissue temperature achieved in thetreatment zone. In some embodiments, this treatment zone temperature isestimated by temperature sensors 170 disposed in a plane mirrored fromthe treatment zone by the antenna. Thus, as energy is deposited into thetreatment zone, the symmetry of the antenna’s power deposition patternenables substantially equivalent power to be deposited into thetreatment zone (typically the nail/nailbed interface). In someembodiments, the system adjusts energy delivery to achieve a desiredheating temperature of the target tissue.

In some embodiments, a control computer is connected to the energydelivery device and the generator and provides a user interface for theuser to control the system. In some embodiments, the control featuresinclude, but are not limited to: selecting an energy level or treatmenttime; selecting a pre-programmed energy delivery protocol; collectingprocedure data (temperature, energy levels); collecting or inputtingpatient-specific data (e.g., name, medical history, images of treatmentarea, insurance provider, payment code; etc.); setting safety protocols;selecting manual versus automatic settings; controlling coolant flow;turning the energy delivery device or generator or control computer onor off; and the like.

The temperature for killing of pathogens is selected based on thecontext of the desired treatment, including the nature of the subjectbeing treated and the pathogen to be killed. In some embodiments, targettissue comprising a pathogen is heated to a temperature from 30° C. to70° C. for a desired period of time (e.g., 40° C. to 60° C.; 45° C. to55° C.; 50° C. to 55° C.; or any ranges or individual temperaturestherein between; e.g., 40° C., 41° C., 42° C., 43° C., 44° C., 45° C.,46° C., 47° C., 48° C., 49° C., 50° C., 51° C., 52° C., 53° C., 54° C.,55° C., 56° C., 57° C., 58° C., 59° C., 60° C., etc.). Experimentsconducted during the development of the technology, employing anonychomycosis model with plate-cultured T. rubrum, demonstratedsignificant growth delay and death of organism at temperatures of 52° C.and 54° C. Additional experiments shows significant pathogen death whentreated for longer time periods at 50° C., with increased killing ateach 10 minute interval from 10 minutes through 90 minutes of treatment.Accordingly, in some embodiment, energy is provided to a nail bed tomaintain a target temperature at the nail bed (e.g., 30° C. to 70° C.)for one or more minutes (e.g., 1 minute, 2 minutes, 5 minutes, 10minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 70minutes, 80 minutes, 90 minutes, or longer, or any time ranges thereinbetween). Regrowth was significantly prevented compared to controls thatdid not undergo temperature treatment (5% regrowth of sub-cultures (2 of40) for 90 minute 50° C. treated cultures compared to 100% regrowth (28of 28) of sub-cultures from untreated (zero minute) samples).

1. A system comprising: a) an energy source; and b) an energy delivery device, said energy delivery device comprising: i) an appendage attachment component having top and bottom portions configured to receive an appendage therebetween; and ii) an antenna electrically coupled to said energy source and positioned above a nail when said appendage attachment component receives an appendage.
 2. The system of claim 1, further comprising: iii) a dielectric layer below said antenna; iv) a first dielectric layer above said antenna; and v) one or more additional dielectric layers above first dielectric layer.
 3. The system of claim 2, wherein said one or more additional dielectric layers comprise a toenail like dielectric layer and a nail-bed like dielectric layer.
 4. The system of claim 1, further comprising one or more thermal sensors.
 5. The system of claim 1, wherein said energy source is a radio-frequency energy generator.
 6. The system of claim 5, wherein said radio-frequency energy generator is a microwave energy generator.
 7. The system of claim 1, wherein said attachment component is a clip, wherein said top and bottom portions are connected by a tensioning component at a proximal end of said clip.
 8. The system of claim 1, wherein said antenna comprises a foil or thin conductor formed in a single- or multi-resonant slot or bowtie configuration on a dielectric substrate.
 9. The system of claim 1, further comprising a user interface.
 10. The system of claim 9, wherein said user interface controls energy delivery from said energy source to said energy delivery device. 11-12. (canceled)
 13. A device comprising: a) an appendage attachment component having top and bottom portions configured to receive an appendage therebetween; b) an antenna positioned above a nail when said appendage attachment component receives an appendage; and c) a connector for electrically coupling said antenna to a radiofrequency energy source.
 14. The device of claim 13, further comprising: d) a dielectric layer below said antenna; e) a first dielectric layer above said antenna; and f) one or more additional dielectric layers above first dielectric layer.
 15. The device of claim 14, wherein said one or more additional dielectric layers comprise a toenail like dielectric layer and a nail-bed like dielectric layer.
 16. The device of claim 13, further comprising one or more thermal sensors.
 17. A method of treating an appendage having nail fungus, comprising: a) attaching an energy delivery device comprising an antenna to said appendage; and b) delivering radio-frequency energy to a nail bed of said appendage.
 18. (canceled)
 19. The method of claim 17, wherein said radio-frequency energy comprises microwave energy.
 20. The method of claim 17, wherein said energy kills nail fungus causing organisms without harming tissue of the appendage. 